1. Field of Invention
The present invention relates generally to a crystal form of morphine sulfate methanolic solvate, preferably having a low amount of α,β-unsaturated ketones (ABUK), and methods for making the same. The invention also relates to pharmaceutical compositions containing a morphine sulfate compound and methods for treating pain using such compositions.
2. Description of Related Art
Morphine is the most abundant of at least 50 alkaloids found in opium, poppy and poppy derivatives, Papaver somniferum. Poppy straw is opium poppy (Papaver somniferum) that is harvested when fully mature and dry, minus the ripe poppy seeds. An agricultural by-product of the poppy seed harvest, the straw was a waste product before the 1930s when a chemical process became available to extract morphine from it. Poppy straw consisting mainly of the capsule became a valuable source of morphine. Today, poppy straw is a major source of many opioids and other alkaloids. It is the source of 90% of the world supply of legal morphine (i.e, for medical and scientific use).
During processing, poppy straw is pulverized and washed many times in water and/or various acids and other chemicals to produce poppy straw concentrate (PSC) or concentrated poppy straw (CPS). Once dried, the concentrate is a beige to brown colored powder and contains salts of various alkaloids. It can range from about 9 to 30 times the morphine concentration of poppy straw. Morphine is generally 8% to 17% of the dry weight of opium, although specially-designed cultivars reach 26% or produce little morphine at all. The latter varieties, including the Przemko and Norman strains of the opium poppy, are used to produce two other alkaloids, thebaine and oripavine, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone and etorphine as well as other types of drugs. At least one manufacturer, Tasmanian Alkaloids, produces both high-morphine and high-thebaine/oripavine types of CPS.
Morphine is produced most predominantly early in the life cycle of the plant and, past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases low quantities of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydrothebaine, and hydrocodone.
Morphine, generally administered in a salt form, is a potent opiate analgesic, for the relief of moderate to severe pain, and has been approved for use for decades. It can be administered as an injectable solution, suppository, capsule, tablet or as an extended release product. Like other opioids, e.g., oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain. Today, morphine sulfate is sold under various trade names including Astramorph PF, Avinza, Depodur, Infumorph, Kadian, MS Contin and Oramorph SR.
Morphine isolated from the opium poppy or compounds derived therefrom are known to contain ABUK compounds. ABUK, in particular morphinone (morphin-6-on), also forms as a result of morphine degradation. These ABUK compounds are considered to be product impurities. Relatively recently, the United States Food and Drug Administration (USFDA) has identified the ABUK moiety as a structural alert for mutagenicity. As a result, USFDA has required manufacturers of opioid products to decrease the levels of genotoxic ABUK impurities in some of their products. For example, in 2008, the USFDA stated its policy that manufacturers of oxycodone hydrochloride products could be approved before they successfully lowered their levels of 14-hydroxycodeinone (an ABUK) as long as each such manufacturer had an “aggressive” plan to eventually meet USFDA's new, lowered, standard for levels of 14-hydroxycodeinone. More recently, in 2010, USFDA required ABUK levels in oxymorphone hydrochloride products to also be reduced. Thus, there is a trend in the art to reduce ABUK levels in opioid products. There remains a need for methods which permit the formation of morphine with low contamination of ABUK impurities.
All references cited herein, including the morphine sulfate products associated with the above-mentioned trade names, are incorporated herein by reference in their entireties.